Clinical characteristics.

AP-4-associated hereditary spastic paraplegia (AP-4-HSP) is a childhood-onset and complex form of hereditary spastic paraplegia. Spastic paraparesis is a universal feature in affected individuals. Manifestations typically begin before age one year, with infants presenting with hypotonia, mild postnatal microcephaly, and delayed developmental milestones. Seizures are common in early childhood, often starting as prolonged febrile seizures. As the disease progresses, older children have intellectual disability that is usually moderate to severe; most affected individuals communicate nonverbally. Neurobehavioral/psychiatric manifestations (e.g., impulsivity, hyperactivity, and inattention) are common. Hypotonia transitions to progressive lower-extremity weakness and spasticity, accompanied by pyramidal signs such as plantar extension, ankle clonus, and hyperreflexia. Although some children achieve independent ambulation, most eventually lose this ability and rely on mobility aids or wheelchairs. In adolescence or early adulthood, spasticity may affect the upper extremities in some individuals but is generally less severe and not significantly disabling. Complications in some individuals include contractures, foot deformities, and bladder and bowel dysfunction. Dysphagia may emerge in advanced stages of the disease.

Diagnosis/testing.

The diagnosis of AP-4-HSP is established in a proband with suggestive findings and biallelic pathogenic variants in AP4B1, AP4E1, AP4M1, or AP4S1 identified on molecular genetic testing.

Management.

Treatment of manifestations: Supportive multidisciplinary care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (including neurology, orthopedics/physiatry, physical therapy, occupational therapy, developmental pediatrics, and speech-language pathology) and clinical genetics.

Surveillance: To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, affected individuals should be evaluated periodically (i.e., every 6-12 months) by their multidisciplinary care specialists.

Genetic counseling.

AP-4-HSP is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an AP4B1, AP4M1, AP4E1, or AP4S1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the AP4B1, AP4M1, AP4E1, or AP4S1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

AP-4-HSP should be suspected in individuals with the following clinical findings, characteristic brain imaging findings, and family history [Verkerk et al 2009; Abou Jamra et al 2011; Moreno-De-Luca et al 2011; Ebrahimi-Fakhari et al 2018; Ebrahimi-Fakhari et al 2020; Ebrahimi-Fakhari et al 2021b; D Ebrahimi-Fakhari, unpublished data].

Clinical findings

• Core clinical features
  • Progressive spastic paraparesis typically with onset between ages 4 and 6 years
  • Early-onset global developmental delay, including delayed motor milestones, failure to achieve or loss of independent ambulation, and impaired or absent speech development
  • Hypotonia in infancy (usually mild)
  • Postnatal microcephaly (usually 2-3 standard deviations below the mean for age and sex)
  • Seizures, including frequent febrile seizures
  • Urinary and stool incontinence
• Less frequent findings
  • Foot deformities (most commonly clubfoot)
  • Episodes of stereotypic laughter
  • Short stature
  • Neurobehavioral/psychiatric manifestations, including short attention span, overactivity, and impulsivity
  • Extrapyramidal manifestations, including dystonia and ataxia

Brain imaging findings

• Characteristic findings
  • Thinning or absence of the anterior commissure
  • Thinning of the corpus callosum (with prominent thinning of the posterior parts)
  • Nonspecific volume reduction of the periventricular white matter, usually with enlargement of the lateral ventricles in colpocephaly configuration
  • Global cerebral volume reduction
  • Ears of the grizzly bear sign [for examples see Ebrahimi-Fakhari et al 2021b]
• Less frequent findings
  • Delayed myelination
  • Bilateral peri-sylvian polymicrogyria
  • Bilateral malrotation of the hippocampi
  • Ears of the lynx sign [for examples see Ebrahimi-Fakhari et al 2021b]
  • Findings suggestive of iron deposition in the globus pallidus and substantia nigra have been identified in six individuals to date [Vill et al 2017, Roubertie et al 2018, Ebrahimi-Fakhari et al 2021b]. These include five individuals with AP4M1-related HSP and one individual with AP4S1-related HSP.

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). About 50% of individuals with AP-4-HSP are from consanguineous families [Ebrahimi-Fakhari et al 2020; D Ebrahimi-Fakhari, unpublished data]. Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of AP-4-HSP is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in AP4B1, AP4E1, AP4M1, or AP4S1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic variants of uncertain significance (or of one known pathogenic variant and one variant of uncertain significance) in any of the genes listed in Table 1 does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

AP-4-associated hereditary spastic paraplegia (AP-4-HSP) is a childhood-onset and complex form of hereditary spastic paraplegia. Spastic paraparesis is a universal feature in affected individuals. Manifestations typically begin before age one year, with infants presenting with hypotonia, mild postnatal microcephaly, and delayed developmental milestones. Seizures are common in early childhood, often starting as prolonged febrile seizures. As the disease progresses, hypotonia transitions to progressive lower-extremity weakness and spasticity, accompanied by pyramidal signs such as plantar extension, ankle clonus, and hyperreflexia. Although some children achieve independent ambulation, most eventually lose this ability and rely on mobility aids or wheelchairs. In adolescence or early adulthood, spasticity may affect the upper extremities in some individuals but is generally less severe and not significantly disabling.

Complications include contractures, foot deformities, and bladder and bowel dysfunction. Dysphagia may emerge in advanced stages of the disease. Dystonia is a prominent extrapyramidal manifestation in early childhood in some, and cerebellar features may become more apparent in later stages. Behavioral manifestations such as impulsivity, hyperactivity, and inattention are frequently observed.

To date, uncomplicated hereditary spastic paraplegia, a pure spastic paraparesis without other neurologic manifestations, has not been reported in individuals with AP-4-HSP.

This summary integrates findings from 156 individuals across 101 families [Ebrahimi-Fakhari et al 2020] and ongoing longitudinal data from a natural history study including 303 individuals from 289 families (NCT04712812) [D Ebrahimi-Fakhari, unpublished data].

Progressive lower-limb spasticity and weakness typically emerge in early childhood and become universal in individuals with AP-4-HSP. The condition usually progresses from mild global hypotonia in infancy (92% of affected individuals, 244/264) to pronounced lower limb spasticity.

• Onset of progressive spastic paraparesis typically occurs between ages four and six years (85%, 256/301).
• In children younger than age four years, lower limb spasticity is present in 60% (47/78).
• In children age four years and older, lower limb spasticity is present in 96% (216/226).

Pyramidal signs, such as hyperreflexia in the lower extremities, ankle clonus, and a positive Babinski sign, are often evident in early childhood. Spasticity initially manifests in the ankles, often accompanied by in-toeing, and progressively moves proximally, further impairing ambulation. Over time, most children with AP-4-HSP require mobility aids or transition to full-time wheelchair use.

Developmental delay is universal. Delayed motor milestones (99%, 277/281) are often the presenting manifestation:

• Sitting (median age: 12 months; Q1-Q3: 9-18 months)
• Crawling (median age: 18 months; Q1-Q3: 12.3-24 months)
• Standing unsupported (median age: 24 months; Q1-Q3: 18-36 months)
• Walking with support (median age: 25 months; Q1-Q3: 20-36 months)

About 45% (110/243) of individuals achieve independent walking (median age: 30 months; Q1-Q3: 24-36 months), a skill that is often lost as the disease progresses.

Speech and language development is significantly impaired or absent (97%, 269/276). The majority of affected individuals communicate nonverbally. Intellectual disability in older children is usually moderate to severe.

Microcephaly becomes evident in infancy in the majority of affected individuals (67%, 73/109) and is often two to three standard deviations below the mean for age and sex.

Seizures often occur in the first two years of life; about 60% (96/160) of individuals have a diagnosis of epilepsy. Seizure types include focal-onset seizures (often with secondary generalization) as well as primary generalized seizures. Status epilepticus has been reported in a significant subset of affected individuals.

About 70% (94/134) of affected individuals, including individuals with and without epilepsy, have seizures in the setting of fever.

In general, seizures become less frequent with age and are often well controlled with standard anti-seizure medications (ASMs). Children with developmental brain malformations, such as polymicrogyria, often require continued treatment with ASMs and may develop medically refractory epilepsy.

Bladder and bowel dysfunction. Urinary incontinence is seen in 81% of affected individuals (112/139) and stool incontinence in 72% (105/146).

Foot deformities, most commonly clubfoot, occur in 50% (118/238) of affected individuals.

Episodes of stereotypic laughter, perhaps indicating a pseudobulbar affect, are a characteristic finding in a subset of individuals (46%, 113/245) [Ebrahimi-Fakhari et al 2018, Ebrahimi-Fakhari et al 2020].

Less frequent findings

• Impaired pain sensation (38%, 36/96) has been reported; however, formal investigations for sensory neuropathy have not been performed.
• Short stature has been observed (34%, 25/74).
• Extrapyramidal manifestations are present in 28% (83/301) of affected individuals, with the most common phenomenology being dystonia (14%, 43/301), followed by ataxia (7%, 20/301). Bradykinesia (3%, 10/301) and rigidity (3%, 8/301) are observed in later stages of the disease.
• Dysphagia may emerge in advanced stages of the disease (24%, 54/224) and may lead to dependence on gastrostomy tube feeding (5%, 4/88).
• Dysarthria (21%, 30/140) impairs speech production.
• Neurobehavioral/psychiatric manifestations have been observed in some individuals, including:
  • Short attention span (33%, 100/301);
  • Overactivity (12%, 35/301);
  • Impulsivity (12%, 37/301).

Prognosis. Natural history data are beginning to emerge. The oldest reported individual is age 55 years [D Ebrahimi-Fakhari, unpublished data].

Phenotype Correlations by Gene

AP-4-HSP is caused by biallelic loss-of-function variants in one of the four genes that encode subunits of the adaptor protein complex 4 (AP-4): β4, ε, μ4, and σ4. Because loss of any one subunit renders the entire complex nonfunctional, biallelic loss-of-function variants in any one of the four genes cause the same molecular defect – loss of AP-4 function – and the same phenotype.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been reported for any of the four genes known to cause AP-4-HSP (AP4B1, AP4E1, AP4M1, and AP4S1).

Nomenclature

Other designations used to refer to AP-4-HSP are listed in Table 2.

Recommendations for the nomenclature of genetic movement disorders, including AP-4-HSP, have been published [Marras et al 2016, Lange et al 2022].

Prevalence

AP-4-HSP is rare. To date, more than 300 individuals with AP-4-HSP are known; 311 have been included in the Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia (HSP) (NCT04712812) (updated 1-6-25).

Families with AP-4-HSP have been reported from North America, South America Europe, the Middle East, China, and the Indian subcontinent [D Ebrahimi-Fakhari, unpublished data].

About half of individuals with AP-4-HSP have consanguineous parents (46%, 142/311) [D Ebrahimi-Fakhari, unpublished data]. Previously reported consanguinity rates were higher likely due to ascertainment bias, as initial reports were focused on families from countries with high rates of consanguinity [Verkerk et al 2009, Abou Jamra et al 2011, Moreno-De-Luca et al 2011]. More recently, AP-4-HSP has been reported in populations with low rates of consanguinity [Ebrahimi-Fakhari et al 2018, Ebrahimi-Fakhari et al 2020].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with AP-4-HSP, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

At present, no treatment prevents, halts, or reverses the progression of the neurologic manifestations of AP-4-HSP.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Affected individuals should be evaluated periodically (i.e., every 6-12 months) by their multidisciplinary care team that includes a neurologist, clinical geneticist, developmental specialist, orthopedic surgeon/physiatrist, physical therapist, occupational therapist, and speech-language pathologist to assess disease progression, maximize ambulation and communication skills, and reduce other manifestations.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Several disease-modifying therapies for AP-4-HSP are currently under development, including AAV9-based gene replacement therapies and small molecule screens.

For AP4M1-related HSP, an AAV9-based gene therapy vector delivering the human gene AP4M1 via a single lumbar intrathecal infusion has successfully completed preclinical development [Chen et al 2023, Dowling et al 2024] and has entered a Phase I/II clinical trial [NCT05518188]. Additionally, individuals in Canada and Spain have received the same vector under expanded access protocols [Dowling et al 2024].

A similar strategy for AP4B1-related HSP has undergone successful preclinical development [Wiseman et al 2024]; however, it has not yet progressed to clinical trials.

Furthermore, a cell-based phenotypic high-throughput screen has identified small molecules capable of restoring protein trafficking in AP-4-deficient cells, including neurons derived from patient-derived induced pluripotent stem cells [Saffari et al 2024]. These compounds are currently in preclinical development.

See Author Notes for information on the Hereditary Spastic Paraplegia Genomic Sequencing Initiative (HSPseq) (NCT05354622).

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

AP-4-associated hereditary spastic paraplegia (AP-4-HSP) is inherited in an autosomal recessive manner.

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an AP4B1, AP4M1, AP4E1, or AP4S1 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an AP4B1, AP4M1, AP4E1, or AP4S1 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an AP4B1, AP4M1, AP4E1, or AP4S1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. To date, individuals with AP-4-HSP are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an AP4B1, AP4M1, AP4E1, or AP4S1 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the AP4B1, AP4M1, AP4E1, or AP4S1 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• It is appropriate to offer AP-4-HSP molecular genetic testing to reproductive partners of individuals known to be heterozygous for a pathogenic variant associated with autosomal recessive AP-4-HSP, particularly if consanguinity is likely. About 50% of individuals with AP-4-HSP are from consanguineous families [Ebrahimi-Fakhari et al 2020; D Ebrahimi-Fakhari, unpublished data].

Prenatal Testing and Preimplantation Genetic Testing

Once the AP4B1, AP4M1, AP4E1, or AP4S1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The adaptor protein complex 4 (AP-4) comprises the subunits β4, ε, μ4, and σ4, which are encoded by the genes AP4B1, AP4E1, AP4M1, and AP4S1, respectively. AP-4 is ubiquitously expressed in human tissues, including the central nervous system [Hirst et al 2013]. At steady state, AP-4 localizes at the subcellular level to the trans-Golgi network (TGN), where it functions in the sorting of transmembrane cargo proteins into transport vesicles for TGN export.

AP-4-associated hereditary spastic paraplegia (AP-4-HSP) is caused by biallelic pathogenic variants in any one of these four genes, as reduction or loss of the mutated subunit reduces the cellular level of the other three subunits, resulting in their degradation by the cell when they are no longer able to be incorporated into a stable complex [Hirst et al 2013, Frazier et al 2016].

AP-4 is part of the well-conserved adaptor protein complexes (APs) family and is associated with the cytosolic side of membranes to identify cargo proteins, and subsequently form vesicle coats that facilitate the budding and transport of vesicles from donor organelles. By recognizing distinct cargo and targeting specific cellular compartments, APs play a crucial role in enabling eukaryotic cells to effectively sort, transport, and recycle proteins along organized intracellular pathways [Guardia et al 2018, Dell'Angelica & Bonifacino 2019]. Specifically, AP-4 mediates the transport of proteins from the TGN to the cell periphery. This function is critical in highly polarized cells such as neurons, where AP-4 is involved in anterograde axonal transport. In the absence of functional AP-4, neurons are especially susceptible to protein mislocalization [Hirst et al 2013, Guardia et al 2018].

Mechanism of disease causation. Recent reports support the hypothesis that (1) AP-4 facilitates the transport of cargo proteins from the TGN; (2) loss-of-function variants in AP-4 subunits lead to its functional impairment, (3) resulting in accumulation of AP-4 cargo proteins in the TGN and (4) their depletion from their target compartments [Hirst et al 2013, Guardia et al 2018, Dell'Angelica & Bonifacino 2019].

Author Notes

The Boston Children's Hospital Hereditary Spastic Paraplegia Research Program is actively involved in clinical research regarding individuals with AP-4-related HSP. The team would be happy to communicate with persons who have any questions regarding diagnosis of AP-4-HSP or other considerations.

Contact:

• Phone: 1-617-355-6388
• Email: ude.dravrah.snerdlihc@hcraeser.psh

To assess the pathogenicity of variants of uncertain significance in any of the four AP-4 subunit genes, high-throughput imaging of subcellular ATG9A distribution in patient-derived cells has been utilized as a diagnostic functional assay on a research basis [Ebrahimi-Fakhari et al 2021a].

The Spastic Paraplegia Centers of Excellence Research Network (SP-CERN) may serve as an additional resource.

• Phone: 1-617-355-6388
• Email: ude.dravrah.snerdlihc@hcraeser.psh
• Web page: https://spcern.childrenshospital.org/

The Hereditary Spastic Paraplegia Genomic Sequencing Initiative (HSPseq) (NCT05354622) was established to identify genetic findings (single-nucleotide changes or copy number variants) in patients with progressive spastic paraplegia and related disorders and to correlate molecular findings with HSP phenotypes. For more information, contact: ude.dravrah.snerdlihc@hcraeser.psh

Acknowledgments

The authors are grateful to their patients and their families for endorsing and supporting their research on AP-4-HSP. The authors also acknowledge grant funding from the CureAP-4 Foundation and the Spastic Paraplegia Foundation.

Author History

Julian Alecu, MD, PhD (2025-current)
Robert Behne; Boston Children's Hospital (2018-2025)
Alexandra K Davies, PhD; University of Cambridge (2018-2025)
Darius Ebrahimi-Fakhari, MD, PhD (2018-current)
Jennifer Hirst, PhD; University of Cambridge (2018-2025)
Luca Schierbaum, MD, PhD (2025-current)

Revision History

• 6 February 2025 (bp) Comprehensive update posted live
• 13 December 2018 (bp) Review posted live
• 21 June 2018 (def) Original submission

Literature Cited

• Abou Jamra R, Philippe O, Raas-Rothschild A, Eck SH, Graf E, Buchert R, Borck G, Ekici A, Brockschmidt FF, Nöthen MM, Munnich A, Strom TM, Reis A, Colleaux L. Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature. Am J Hum Genet. 2011;88:788-95. [PMC free article: PMC3113253] [PubMed: 21620353]
• Chen X, Dong T, Hu Y, De Pace R, Mattera R, Eberhardt K, Ziegler M, Pirovolakis T, Sahin M, Bonifacino JS, Ebrahimi-Fakhari D, Gray SJ. Intrathecal AAV9/AP4M1 gene therapy for hereditary spastic paraplegia 50 shows safety and efficacy in preclinical studies. J Clin Invest. 2023;133:e164575. [PMC free article: PMC10178841] [PubMed: 36951961]
• Dell'Angelica EC, Bonifacino JS. Coatopathies: genetic disorders of protein coats. Annu Rev Cell Dev Biol. 2019;35:131-68. [PMC free article: PMC7310445] [PubMed: 31399000]
• Dowling JJ, Pirovolakis T, Devakandan K, Stosic A, Pidsadny M, Nigro E, Sahin M, Ebrahimi-Fakhari D, Messahel S, Varadarajan G, Greenberg BM, Chen X, Minassian BA, Cohn R, Bonnemann CG, Gray SJ. AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient. Nat Med. 2024;30:1882-7. [PMC free article: PMC11271397] [PubMed: 38942994]
• Ebrahimi-Fakhari D, Alecu JE, Brechmann B, Ziegler M, Eberhardt K, Jumo H, D'Amore A, Habibzadeh P, Faghihi MA, De Bleecker JL, Vuillaumier-Barrot S, Auvin S, Santorelli FM, Neuser S, Popp B, Yang E, Barrett L, Davies AK, Saffari A, Hirst J, Sahin M. High-throughput imaging of ATG9A distribution as a diagnostic functional assay for adaptor protein complex 4-associated hereditary spastic paraplegia. Brain Commun. 2021a;3:fcab221. [PMC free article: PMC8557665] [PubMed: 34729478]
• Ebrahimi-Fakhari D, Alecu JE, Ziegler M, Geisel G, Jordan C, D'Amore A, Yeh RC, Akula SK, Saffari A, Prabhu SP, Sahin M, Yang E; International AP-4-HSP Registry and Natural History Study. Systematic analysis of brain MRI findings in adaptor protein complex 4-associated hereditary spastic paraplegia. Neurology. 2021b;97:e1942-e1954. [PMC free article: PMC8601212] [PubMed: 34544818]
• Ebrahimi-Fakhari D, Cheng C, Dies K, Diplock A, Pier DB, Ryan CS, Lanpher BC, Hirst J, Chung WK, Sahin M, Rosser E, Darras B, Bennett JT; CureSPG47. Clinical and genetic characterization of AP4B1-associated SPG47. Am J Med Genet A. 2018;176:311-8. [PubMed: 29193663]
• Ebrahimi-Fakhari D, Teinert J, Behne R, Wimmer M, D'Amore A, Eberhardt K, Brechmann B, Ziegler M, Jensen DM, Nagabhyrava P, Geisel G, Carmody E, Shamshad U, Dies KA, Yuskaitis CJ, Salussolia CL, Ebrahimi-Fakhari D, Pearson TS, Saffari A, Ziegler A, Kölker S, Volkmann J, Wiesener A, Bearden DR, Lakhani S, Segal D, Udwadia-Hegde A, Martinuzzi A, Hirst J, Perlman S, Takiyama Y, Xiromerisiou G, Vill K, Walker WO, Shukla A, Dubey Gupta R, Dahl N, Aksoy A, Verhelst H, Delgado MR, Kremlikova Pourova R, Sadek AA, Elkhateeb NM, Blumkin L, Brea-Fernández AJ, Dacruz-Álvarez D, Smol T, Ghoumid J, Miguel D, Heine C, Schlump JU, Langen H, Baets J, Bulk S, Darvish H, Bakhtiari S, Kruer MC, Lim-Melia E, Aydinli N, Alanay Y, El-Rashidy O, Nampoothiri S, Patel C, Beetz C, Bauer P, Yoon G, Guillot M, Miller SP, Bourinaris T, Houlden H, Robelin L, Anheim M, Alamri AS, Mahmoud AAH, Inaloo S, Habibzadeh P, Faghihi MA, Jansen AC, Brock S, Roubertie A, Darras BT, Agrawal PB, Santorelli FM, Gleeson J, Zaki MS, Sheikh SI, Bennett JT, Sahin M. Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia. Brain. 2020;143:2929-44. [PMC free article: PMC7780481] [PubMed: 32979048]
• Fink JK. Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. Acta Neuropathol. 2013;126:307-28. [PMC free article: PMC4045499] [PubMed: 23897027]
• Frazier MN, Davies AK, Voehler M, Kendall AK, Borner GH, Chazin WJ, Robinson MS, Jackson LP. Molecular basis for the interaction between AP4 beta4 and its accessory protein, tepsin. Traffic. 2016;17:400-15. [PMC free article: PMC4805503] [PubMed: 26756312]
• Guardia CM, De Pace R, Mattera R, Bonifacino JS. Neuronal functions of adaptor complexes involved in protein sorting. Curr Opin Neurobiol. 2018;51:103-110. [PMC free article: PMC6410744] [PubMed: 29558740]
• Hirst J, Irving C, Borner GH. Adaptor protein complexes AP-4 and AP-5: new players in endosomal trafficking and progressive spastic paraplegia. Traffic. 2013;14:153-64. [PubMed: 23167973]
• Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519-22. [PubMed: 28959963]
• Lange LM, Gonzalez-Latapi P, Rajalingam R, Tijssen MAJ, Ebrahimi-Fakhari D, Gabbert C, Ganos C, Ghosh R, Kumar KR, Lang AE, Rossi M, van der Veen S, van de Warrenburg B, Warner T, Lohmann K, Klein C, Marras C; on behalf of the Task Force on Genetic Nomenclature in Movement Disorders. Nomenclature of genetic movement disorders: recommendations of the International Parkinson and Movement Disorder Society Task Force - an update. Mov Disord. 2022;37:905-35. [PubMed: 35481685]
• Manickam K, McClain MR, Demmer LA, Biswas S, Kearney HM, Malinowski J, Massingham LJ, Miller D, Yu TW, Hisama FM; ACMG Board of Directors. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23:2029-37. [PubMed: 34211152]
• Marras C, Lang A, van de Warrenburg BP, Sue CM, Tabrizi SJ, Bertram L, Mercimek-Mahmutoglu S, Ebrahimi-Fakhari D, Warner TT, Durr A, Assmann B, Lohmann K, Kostic V, Klein C. Nomenclature of genetic movement disorders: recommendations of the International Parkinson and Movement Disorder Society task force. Mov Disord. 2016;31:436-57. [PubMed: 27079681]
• Moreno-De-Luca A, Helmers SL, Mao H, Burns TG, Melton AM, Schmidt KR, Fernhoff PM, Ledbetter DH, Martin CL. Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability. J Med Genet. 2011;48: 141-4. [PMC free article: PMC3150730] [PubMed: 20972249]
• Raza MH, Mattera R, Morell R, Sainz E, Rahn R, Gutierrez J, Paris E, Root J, Solomon B, Brewer C, Basra MA, Khan S, Riazuddin S, Braun A, Bonifacino JS, Drayna D. Association between rare variants in AP4E1, a component of intracellular trafficking, and persistent stuttering. Am J Hum Genet. 2015; 97: 715-25. [PMC free article: PMC4667129] [PubMed: 26544806]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Roubertie A, Hieu N, Roux CJ, Leboucq N, Manes G, Charif M, Echenne B, Goizet C, Guissart C, Meyer P, Marelli C, Rivier F, Burglen L, Horvath R, Hamel CP, Lenaers G. AP4 deficiency: a novel form of neurodegeneration with brain iron accumulation? Neurol Genet. 2018;4:e217. [PMC free article: PMC5820597] [PubMed: 29473051]
• Saffari A, Brechmann B, Böger C, Saber WA, Jumo H, Whye D, Wood D, Wahlster L, Alecu JE, Ziegler M, Scheffold M, Winden K, Hubbs J, Buttermore ED, Barrett L, Borner GHH, Davies AK, Ebrahimi-Fakhari D, Sahin M. High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia. Nat Commun. 2024;15:584. [PMC free article: PMC10794252] [PubMed: 38233389]
• Verkerk AJ, Schot R, Dumee B, Schellekens K, Swagemakers S, Bertoli-Avella AM, Lequin MH, Dudink J, Govaert P, van Zwol AL, Hirst J, Wessels MW, Catsman-Berrevoets C, Verheijen FW, de Graaff E, de Coo IF, Kros JM, Willemsen R, Willems PJ, van der Spek PJ, Mancini GM. Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy. Am J Hum Genet. 2009;85:40-52. [PMC free article: PMC2706965] [PubMed: 19559397]
• Vill K, Müller-Felber W, Alhaddad B, Strom TM, Teusch V, Weigand H, Blaschek A, Meitinger T, Haack TB. A homozygous splice variant in AP4S1 mimicking neurodegeneration with brain iron accumulation. Mov Disord. 2017;32:797-9. [PubMed: 28150420]
• Wiseman JP, Scarrott JM, Alves-Cruzeiro J, Saffari A, Böger C, Karyka E, Dawes E, Davies AK, Marchi PM, Graves E, Fernandes F, Yang ZL, Coldicott I, Hirst J, Webster CP, Highley JR, Hackett N, Angyal A, Silva T, Higginbottom A, Shaw PJ, Ferraiuolo L, Ebrahimi-Fakhari D, Azzouz M. Pre-clinical development of AP4B1 gene replacement therapy for hereditary spastic paraplegia type 47. EMBO Mol Med. 2024;16:2882-917. [PMC free article: PMC11554807] [PubMed: 39358605]